HK1144907A - Oral nicotine formulation buffered with amino acid - Google Patents

Description

Oral nicotine formulation buffered with amino acids

Technical Field

The present invention relates to nicotine-containing pharmaceutical formulations for intraoral delivery of nicotine to a subject. The formulation comprises one or more amino acids as a buffer. Of particular interest are endogenous amino acids. Also contemplated are methods and systems for delivering nicotine and uses and preparations of the formulations.

Background

Nicotine dependence and its reduction is a desirable goal. In recent years, with the recognition of the detrimental effects of tobacco smoking, government agencies and various health groups and other related organizations have developed a number of activities and programs to advertise information about the detrimental health effects caused by tobacco smoking. Moreover, in recognition of this detrimental effect, there have been many programs directed to attempts to reduce the incidence of smoking.

Nicotine is an organic compound and is the main alkaloid of tobacco. Nicotine is a major addictive ingredient in tobacco used in cigarettes, cigars, snuff and the like. Nicotine is also an addictive drug and smokers characteristically exhibit a strong tendency to relapse after a period of successful smoking cessation. Nicotine is the second most commonly used drug in the world, behind caffeine in coffee and tea.

The major problem with 000 smoking of tobacco is its enormous health impact. Smoking-related illness is estimated to cause death in 3-4 million people each year. According to the United States Central for disease control and prevention report (tobacco smoking and installing adults-United States, 1995.MMWR 1997; 46: 1217-. Indeed, it is now recognized that excessive smoking is a major health problem worldwide. This terrible consequence of tobacco smoking has forced many medical associations and health authorities to take very powerful actions against the use of tobacco.

Even though tobacco smoking is decreasing in many developed countries today, it is difficult to foresee how society can get rid of this world's second most commonly used drug. In many countries, particularly in less developed countries, the incidence of smoking is still rising.

The most advantageous thing a heavy smoker can do is to stop smoking completely or at least reduce the frequency with which he/she smokes. Experience has shown, however, that most smokers find this extremely difficult, as smoking tobacco generally results in dependence disorders or addiction. The world health organization ("WHO") has a diagnosis in its International Classification of Disorders called "tobacco dependence". Other organizations such as the American psychiatric association (American psychiatric association) are known as nicotine dependence. It is generally accepted that these difficulties in quitting smoking are due to the dependence of those heavy smokers on nicotine. However, the most important risk factors associated with health are substances formed during the combustion of tobacco, such as carcinogenic tar products, carbon monoxide, N-nitrosamines, aldehydes and hydrocyanic acid.

Action of Nicotine

Nicotine is an addictive toxic alkaloid C derived from tobacco plants₅H₄NC₄H₇NCH₃. Nicotine is also used as an insecticide. Administration of nicotine (e.g., in the form of smoking a cigarette, cigar, or pipe) can create a pleasant sensation to the smoker. However, smoking is harmful to health, and there is a need to formulate a method for promoting smoking cessation and/or replacement smoking in a pleasant and harmless manner instead of administering nicotine.

On smoking a cigarette, nicotine is rapidly absorbed into the smoker's blood and reaches the brain within about ten seconds after inhalation. The rapid absorption of nicotine immediately results in satisfaction or pleasure for the smoker. Satisfaction typically persists during smoking of the cigarette, and for a period of time thereafter. This toxic, carcinogenic, and addictive nature of smoking provides a strong incentive to develop methods, compositions, and devices that can be used to break the bad habit of smoking.

Nicotine substitute

One way to reduce smoking is to provide nicotine in a non-smoking form or manner, and several products have been developed to meet this need. Nicotine-containing formulations have become the primary therapeutic agent for tobacco dependence in recent years.

The success rate of achieving reduced incidence of smoking using currently known products is relatively small. The current state of the art includes both behavioral and pharmacological approaches. Of the tobacco smokers who initially used certain behavioral or pharmacological approaches to quit smoking, with individual reductions in the incidence of smoking, more than 80% of tobacco smokers often revisit and return to smoking bad habit of their original rate within a period of about a year.

As an aid to those who wish to quit smoking, nicotine substitutes are available in some manner and form on the market. Several methods and means for eliminating the urge to use tobacco in a subject have been described, including the step of administering to the subject nicotine or a derivative thereof as described, for example, in the following patents: U.S. patent application No. 5,810,018 (oral nicotine-containing spray), U.S. patent application No. 5,939,100 (nicotine-containing micro spheres), and U.S. patent application No. 4,967,773 (nicotine-containing lozenge).

Nicotine-containing nasal drops have been reported (Russell et al,British Medical Journalvol.286, p.683 (1983); the subject of Jarvis et al,Brit.J.of Addictionvol.82, p.983 (1987)). However, nasal drops are difficult to administer and inconvenient to use at work or other public places. Administration of nicotine by spray delivery directly into the nasal cavity is known from us patent application numbers 4,579,858, DE 3241437 and WO 93/12764. However, there may be local irritation of the nasal cavity with a nicotine formulation for nasal cavity. Such administration difficulties can also lead to unpredictable amounts of nicotine being administered.

The use of skin patches for transdermal administration of nicotine has been reported (Rose, in pharmaceutical Treatment of Tobacco Dependence, (1986) pp.158-166, Harvard Univ.Press). The nicotine-containing skin patches widely used today cause local irritation and the absorption of nicotine is slow and influenced by the skin blood flow rate.

Additionally, inhalation devices that simulate cigarettes are known for inhalation of nicotine vapors, as illustrated in U.S. patent application No. 5,167,242. The means and methods address problems associated with nicotine addiction.

A successful nicotine-based product useful as a smoking substitute and/or smoking cessation aid is chewing gumThis product is one of the first nicotine replacement forms that is approved by the Food and Drug Administration (FDA) and remains one of the most commonly used nicotine replacement.Chewing gum has been marketed for several years in about 60 countries. In such chewing gums, nicotine is present as a complex with an insoluble cation exchanger (ion exchange resin) dispersed in the chewing gum matrix. The nicotine is slowly released from the chewing gum due to chewing and according to the chewing technique (i.e. slow chewing or aggressive chewing) after about 30 minutes a similar plasma level can be reached as when smoking a cigarette. Patents related to this product are, for example, U.S. patent application No. 3,877,468, U.S. patent application No. 3,901,248, and U.S. patent application No. 3,845,217.

Prior art and problems thereof

WO 02/102357 discloses a nicotine-containing chewing gum with a coating. The chewing gum provides improved transmucosal absorption of nicotine in the oral cavity. Thereby achieving better cigarette-like satisfaction and more rapid reduction in the desire to smoke. However, most of the buffering agents proposed in WO 02/102357 have an off-taste, which requires one or more flavoring agents to be added to the chewing gum to mask. Some glycinates are mentioned in the buffer list, but there is no mention of whether these salts have any undesirable taste.

WO 2005/023227 discloses nicotine-containing compositions wherein nicotine is absorbed into and/or onto cellulose of non-seed biological origin, in particular from algae, bacteria and/or fungi. Most of the buffers proposed in WO 2005/023227 also have an unpleasant taste, as in WO 02/102357. Some glycinates are mentioned in the buffer list, but there is no mention of whether these salts have any undesirable taste.

Oqawa Tazuko et al, "screening bitter taste inhibitors for quinine: the use of molecularly imprinted polymers (Screening of bittering-proofing agents for quinines; The use of molecular imprinted polymers; Journal of pharmaceutical Sciences, Vol.94, No.2(Feb 2005), 353-362) suggests that a few amino acids may suppress The bitter taste of quinine, but most amino acids do not. Nonetheless, Oqawa et al do not disclose any utility of amino acids as buffering agents in nicotine-containing formulations. Quinine and nicotine are very different chemically and pharmacologically, which means that the teachings regarding quinine do not apply equally to nicotine.

The problem of the buffer giving off-taste can be seen in all other nicotine-containing pharmaceutical formulations delivered orally, such as mouth sprays, chewable tablets, lozenges, chewing gums, capsules, lipid-filled micro-gels, oral films and different confectionary-type formulations.

Thus, there is a need for improved orally delivered nicotine-containing pharmaceutical formulations to avoid the negative taste from the buffer used. Many of the buffer compounds disclosed as novel and inventive in this patent application are particularly useful because they are endogenous amino acids, i.e. they are already present in the human body.

To date, there has been no disclosure of the utility of amino acids as buffering agents in nicotine-containing pharmaceutical formulations. US 5,733,572 discloses aerated microspheres which may also contain nicotine and certain amino acids as shown in long and unimorphized wash lists, but the amino acids are not used for buffering purposes but for achieving a depot effect.

Disclosure of Invention

When formulating medical products intended to dissolve in the oral cavity, their organoleptic characteristics are essential requirements. In addition to this, in many cases it is necessary to reach an optimal pH in the oral cavity in order to be able to achieve a sufficiently rapid absorption of the active ingredient. The pH can be adjusted by using a buffer in the product. However, the number of pharmaceutically suitable buffers is limited, and some of the most commonly used buffers have a unique off-taste. Therefore, one or more flavoring agents are often added to the formulation to mask these off-flavors. In addition, flavoring agents may also be used in the formulation to achieve a product with a pleasant taste. The possibility of using buffers without or with less off-taste facilitates the formulation work and reduces the complexity of the seasoning process. Many amino acid type buffers are not unpleasant to taste inherently and therefore, the present inventors have found that the use of such excipients in orally ingested nicotine-containing products is beneficial.

Another important criterion when selecting a buffer in a nicotine-containing formulation is toxicity. Many common amino acids can be classified as harmless because they are present in large amounts (several grams per day) in common nutrients.

Other advantages of using amino acids as buffering agents in nicotine-containing formulations include: there is no unpleasant odor, many amino acids of interest are monograph in USP/NF and ph.

In view of the above-described shortcomings known in the art in attempting to deliver nicotine to a subject to achieve transmucosal absorption of nicotine within the oral cavity of the subject, the present invention provides new and improved products, systems, and methods for the subject to ingest nicotine across the oral mucosa while avoiding the undesirable taste from the buffer used.

It is an object of the present invention to provide practical and effective products and methods and systems for nicotine ingestion by a subject, and to avoid the disadvantages of these previously known products and methods.

The present invention provides an oral formulation comprising nicotine in any form, which formulation is buffered with at least one amino acid and which further comprises a pH adjusting compound if the pH adjusting ability of the at least one amino acid is insufficient.

The present invention also provides a method for delivering nicotine in any form to a subject, the method comprising: administering an oral formulation comprising nicotine in any form to the oral cavity of a subject and, if desired, allowing nicotine in any form in the oral formulation to be released in the oral saliva and absorbed into the systemic circulation of the subject, and methods for making the same. In mouth sprays, nicotine can be used directly, so it does not need to be released in saliva as described above. Thus, the phrase "if desired" is inserted in the preceding sentence, and in the following and in the claims corresponding sentences.

The present invention also provides a method for achieving a reduction in the urge to smoke or use a tobacco-containing material and/or to provide smoking satisfaction in the absence of smoking, the method comprising the steps of: at least partially replacing the tobacco-containing material with the oral formulation described above, administering to the subject an oral formulation comprising nicotine in any form to the oral cavity of the subject, and if desired, allowing nicotine in any form in the oral formulation to be released in the oral saliva and absorbed by the subject.

Furthermore, the present invention provides a system for delivering nicotine in any form to a subject, the system comprising said oral formulation and at least one other means for achieving reduction in the urge to smoke or use tobacco, and a system for achieving reduction in the urge to smoke or use tobacco and/or providing smoking satisfaction without smoking, the system comprising the above oral formulation and at least one method for achieving reduction in the urge to smoke or use tobacco. The system may be one in which at least the other method is selected from the group consisting of administration by mouth sprays, nasal sprays, transdermal patches, inhalation devices, lozenges, tablets and parenteral methods, subcutaneous methods and transmucosal methods; or other tobacco use methods.

By using an amino acid as the sole buffering agent or as the main buffering agent in the oral formulation, the above-mentioned problems regarding the unpleasant taste of the used buffering agent are solved. Furthermore, such a buffer as described above may be considered satisfactory from the viewpoint of toxicity.

Detailed Description

Definition of

As used herein, the term "oral formulation" or similar terms is intended to mean all formulations suitable for placement in the oral cavity for delivery of nicotine generally to the oral mucosa.

The term "intraoral delivery" is intended herein to mean delivery into the systemic blood circulation by absorption of the active principle by any tissue of the oral cavity.

The term "complete reduction" or "complete" is intended herein to mean complete reduction or substantially complete reduction.

The term "controlled release" is intended to mean the release of nicotine from an oral formulation in the oral cavity of a subject whereby the amount of nicotine released is controlled by active sucking or other manipulation of the oral formulation.

The term "slow release" is intended to mean that nicotine is released from an oral formulation after a period of sucking or other manipulation (e.g., minutes to an hour).

The term "unit formulation" is intended to mean an oral dosage unit.

The term "transient" is intended to mean a non-permanent change, on the basis of which a relevant state (e.g. a biological or physiological state) will return after a period of time to its value or behavior prior to the change.

The terms "buccal" and "oral cavity" are intended herein to refer to all tissues or any portion of tissues within the oral cavity.

Useful oral formulations

Most dosage forms intended for oral delivery of nicotine benefit from the use of selected amino acids as the sole or primary buffer. Such formulations include, for example, mouth sprays, chewing gums, tablets, melt tablets, lozenges, hard candies, chewy candies, gummies, capsules, mouth films and liquids, and powders for oral and pulmonary inhalation.

Some formulations are oral sprays. These formulations are discrete dosage forms that can be used to achieve rapid absorption of nicotine across the oral mucosa. The oral spray may be sprayed directly into the oral cavity or sublingually. The following example 3 discloses the preparation of an oral spray according to the invention.

The amount of gum base in the chewing gum according to the invention is 15-80% by weight, and preferably about 40-80% by weight of the total chewing gum core. The amount of chewing gum base used for slow release of nicotine is generally in a higher range when nicotine is used as such or in absorbed form.

The gum base may be of any conventional nature known in the art. For example, it may comprise a chewing gum base of natural or synthetic origin, readily available from commercial sources. Natural gum bases include, for example, chicle, jelutong (jelutong), riqikasby (lechi de caspi), sorafen (soh), sierra (siak), katakau (katiau), sorwa (sorwa), balata (balata), pandar (pendare), malaya (malaya) and peach gum, natural kojike (cautchouc) and natural resins such as dammar and mastic. The synthetic gum base is a mixture of:

elastomers (e.g. polymers and/or chewable substances),

Plasticizers (e.g. resins, elastomers and/or solvents),

Fillers (e.g. texturizing agents and/or water-insoluble adjuvants),

Softeners (e.g. fats),

An emulsifier, a,

-a wax,

-an antioxidant, a,

And antiadherents (e.g. vinyl polymers and/or hydrophilic resins)

Examples of other gum bases are gums including agar, alginate, gum arabic, locust bean gum, carrageenan, ghatti gum, guar gum, karaya gum, pectin, tragacanth gum, locust bean gum, gellan gum, and xanthan gum.

Examples of gelling agents include gum arabic, starch, gelatin, agar and pectin.

When nicotine in any form and one or more buffering agents are incorporated into a chewing gum base according to the present invention, a wide variety of chewing gum compositions and amounts of chewing gum base may be employed.

Chewing gum products that differ in nicotine level, nicotine distribution and other additives can be prepared according to consumer preference and purpose of use.

The following are examples of chewing gums, tablets, melt tablets, mouth sprays, soft capsules, hard candies, oral films, gummies and chewy candies that may be used in accordance with the present invention. Other usable embodiments are also conceivable on the basis of the examples.

Buffering agent

The absorption of nicotine from the oral cavity into the systemic circulation is dependent on the pH of saliva, the pH of plasma and the acid-base equilibrium of nicotine, which is about pKa 7.8 at 37 ℃. Assuming a saliva pH of 6.8, only about 10% of the nicotine will be in the uncharged base form. Therefore, in order to facilitate the absorption of nicotine in the free base form (which is the form absorbed primarily through the mucous membranes), the pH of saliva must be increased. At a pH of 9.0, more than 90% of the nicotine will be in the free base form which is readily absorbed.

According to the present invention, an oral formulation is buffered by using a substance, formulation or other means which at least partially comprises an amino acid, preferably an endogenous amino acid and/or a salt thereof.

As noted above, many amino acid type buffers do not have an unpleasant inherent taste. Furthermore, from a toxicity point of view, many common amino acids, especially endogenous amino acids, can be classified as harmless, since they are present in large amounts (several grams per day) in common nutrients.

In selecting amino acids that can be used as buffering agents in nicotine-containing formulations, it should be preferred to use at least some of the following criteria:

1) the pKa range is 8,0-9,6 (since the system should be buffered at a pH range above the pKa value of nicotine at 25 ℃).

2) The solubility in water is greater than about 10 g/kg.

3) Are useful from a toxicity point of view.

4) Preferably already used as a buffer in nicotine-free pharmaceutical formulations.

The most useful amino acids are listed in table 1 below.

TABLE 1 particularly useful amino acids。

Compound (I)	CAS number	pKa value (range 8-9, 6)	Solubility in Water, g/kg
				Arginine	74-79-3	9,00	182,6a)
Asparagine	70-47-3	8,73	25,1
				Glutamic acid	56-86-0	9,58	8,61a)b)
Glutamine	56-85-9	9,00	42
				Glycine	56-40-6	9,58	250,9
Histidine	71-00-1	9,09	43,5
				Isoleucine	73-32-5	9,60	34,2
Leucine	61-90-5	9,58	22,0
				Lysine	56-97-1	9,16	Is very easy to dissolvea)b)
Methionine	63-68-3	9,08	56
				Phenylalanine	63-91-2	9,09	27,9

Compound (I)	CAS number	pKa value (range 8-9, 6)	Solubility in Water, g/kg
				Serine	56-45-1	9,05	50,2
Threonine	72-19-5	8,96	98,1
				Valine	72-18-4	9,52	88，5
Cysteic acid	13100-82-8	8,70	Is very easy to dissolve
				N-glycylglycine	556-50-3	8,10	No information
Ornithine	70-26-8	8,78	Is very easy to dissolve

a) Have been reported to be useful as buffering agents in non-nicotine containing pharmaceutical formulations.

b) Low solubility in water or uncertain value.

Data for amino acid labeling are taken from Handbook of chemistry and Physics, 85 th edition; table 7-1 ("20 standard Amino acids which are the basic components of the protein of the basic components of the proteins of the biological interactions) and Table 7-2 (" biochemically valuable Amino acids and related compounds ").

The buffering is designed to achieve a short buffer of the saliva of a subject at elevated pH during thawing, disintegration or dissolution of the oral formulation. Since this change is brief, the pH will return to its normal value over time.

By utilizing said change (here an increase) of the saliva pH, the transmucosal absorption of nicotine in the oral cavity is changed, e.g. increased, compared to the absorption of nicotine when the saliva is not buffered according to the invention. In addition, since the transmucosal absorption of nicotine according to the invention in the oral cavity is faster than the absorption of nicotine without buffering according to the invention, a smaller amount of nicotine will be swallowed to reach the gastrointestinal (G.I.) tract. Nicotine reaching the gastrointestinal tract will undergo first pass metabolism, which will reduce the total amount of intact nicotine that can be absorbed. This means that nicotine not administered with a buffer will generally be less bioavailable than nicotine administered with a buffer.

Other embodiments of the invention include oral dosage forms buffered with a combination of an amino acid and another buffering agent or pH-adjusting compound, preferably selected from the group consisting of: alkali metal or ammonium carbonates (including bicarbonates or sesquicarbonates), such as potassium or sodium, phosphates, glycerophosphates or citrates, and mixtures thereof.

Other embodiments may encompass the use of amino acids and different phosphate systems, such as trisodium phosphate, disodium phosphate; and tripotassium phosphate, dipotassium phosphate, and calcium hydroxide, sodium glycinate, tromethamine and mixtures thereof.

Alkali metal carbonates and phosphates are preferred as another buffering agent or pH adjusting compound.

To further increase the buffering capacity without a corresponding increase in pH, one may in particular embodiments use a second buffer or an auxiliary buffer, such as a sodium bicarbonate or potassium bicarbonate buffer, in the first buffer. Additionally, a strong base, such as sodium hydroxide, may be added to the formulation in order to increase the alkaline nature of the formulation. Thus, it should be strived to maintain a pleasant taste. The second buffer or auxiliary buffer may be selected from alkali metal bicarbonates which are preferred for this purpose. Thus, other embodiments of the invention may comprise mixtures of amino acids and alkali metal carbonates or phosphates and alkali metal bicarbonates. Some of the mixing ratios that are available are provided in the examples below.

In particular embodiments, the amount of buffer and optional pH-adjusting compound in the oral formulation is preferably sufficient to temporarily maintain the pH of saliva in the oral cavity above 7, e.g., between pH 7 and 10.

The nicotine may be administered in different forms, for example in the form of different complexes or salts. The amount of buffer and optional pH adjusting compound required to achieve pH increase for different nicotine administration forms can be readily calculated by one skilled in the art. The extent and duration of the pH increase depends on the type and amount of buffer used and those further described in the following paragraphs.

Active ingredient

According to the invention, the oral formulation of the invention comprises nicotine in any form, e.g. in the form of a free base, a salt or a complex.

With respect to nicotine, it is intended to include nicotine (3- (1-methyl-2-pyrrolidinyl) -pyridine), with respect to its base form, including synthetic nicotine as well as nicotine extracts from tobacco plants or parts thereof (e.g., individual nicotiana species or combinations thereof); or a pharmaceutically acceptable salt thereof.

The nicotine compound should be in a form that is saliva-dissolvable or that allows for ready release of nicotine into the oral saliva, and also allows for subsequent ready absorption of nicotine from the oral saliva into the systemic circulation of the subject. When nicotine is predominantly in the form of Nicotine Resinate Complex (NRC), its nicotine release can be improved in the presence of a buffer.

In a preferred embodiment, the nicotine in any form is selected from the group consisting of nicotine in free base form, nicotine salts, nicotine derivatives such as nicotine cation exchangers, nicotine inclusion complexes or any non-covalently bound nicotine, nicotine bound to zeolites, nicotine bound to cellulose or starch microspheres, and mixtures thereof.

Many nicotine salts are known and may be used, for example the salts provided in table 2, preferably mono-tartrate, bitartrate (also known as acid tartrate or bitartrate dihydrate), citrate, malate and/or hydrochloride.

Table 2 usable acids for nicotine salt formation

^*Recommended molar ratio in preparation

The inclusion complex may be a nicotine-cyclodextrin (1-1) complex, such as nicotine- β -cyclodextrin.

Suitable cation exchangers are given in table 3 below and are further disclosed in U.S. patent application No. 3,845,217. Preferred are polyacrylate nicotine cation exchangers, such as the Amberlite series from Rohm & Haas.

Representative cation exchangers of Table 3

One or more additives may be added to the oral formulation of the present invention. Additives are further described in the following paragraph "other additives for oral formulations".

Amount and distribution of nicotine in oral formulations

Any form of nicotine according to the invention may be formulated to provide a subject with an amount that achieves a certain effect. The effect may be to provide smoking satisfaction without smoking. Another effect of administering nicotine in any form may be to reduce the urge to smoke or use tobacco.

The effect may also be to both reduce the urge and provide smoking satisfaction without smoking. The amount of nicotine should be sufficient to provide such an effect to the subject. Of course, the amount may vary from person to person.

Examples of oral formulations according to the present invention include such examples: in this example nicotine in any form is present in an amount of 0.05-8mg calculated as free base form nicotine per unit dose of oral formulation. In various embodiments, the amount may include 0.1, 0.5, 1,2, 3, 4,5, 6, or 8mg, calculated as free base form nicotine per unit dose.

Other preferred embodiments may include embodiments in which: in this example, nicotine in any form is present in an amount of 0.5-6mg calculated as free base form nicotine per unit dose of oral formulation.

More preferred embodiments comprise nicotine in any form in an amount of 0.5-5mg calculated as nicotine in free base form per unit dose of oral formulation.

In various embodiments, any form of nicotine can be distributed in an oral formulation. A different distribution of nicotine throughout the oral formulation would mean that nicotine is administered to the subject in a different manner. This therefore offers several possibilities to adjust the composition of the oral preparation to the different needs of different subjects based on the desire to smoke or use tobacco. Various such embodiments are disclosed in the following examples.

Other additives for oral formulations

A strong base such as sodium hydroxide may be added to the formulation to make the formulation slightly alkaline.

Other additives may optionally be added to the oral formulation. The optional additives include at least one or more additives selected from the group consisting of: solvents such as ethanol and water; co-solvents, such as propylene glycol; stabilizers, for example preservatives, such as antioxidants; softeners such as sorbitol and glycerin; thickeners, such as colloidal silica; binders, such as xanthan gum; fillers such as mannitol, isomalt, cocoa powder and crospovidone; solubilizers such as polysorbate 80 and Atmos 300; rubber, lipid barriers such as sucrose fatty acid esters and hydrogenated vegetable oils; film-forming agents such as porcine gelatin, pullulan, carrageenan, pectin, locust bean gum and xanthan gum; emulsifiers such as pectin, soy lecithin, glyceryl monostearate, castor oil and poloxamers; glidants, such as colloidal silicon dioxide; lubricants, such as magnesium stearate; coating agents such as castor oil and sorbitol; thawing media, such as vegetable oils; sweeteners, flavoring agents, fragrances, cooling agents, enhancers, colorants, vitamins, minerals, fluorine, breath freshening agents, tooth whitening agents, and mixtures thereof. According to the present invention, at least one of such additives may optionally be added to the product.

Enhancers must be added to enhance transmucosal absorption of nicotine from the oral cavity.

Sweeteners must be added to improve taste. Sweetening agents include one or more of synthetic or natural sugars, i.e. sugars in any form suitable for use as sweetening agents, and so-called artificial sweeteners, e.g. saccharin, saccharin sodium, aspartame, e.g.Acesulfame or acesulfame K, acesulfame potassium, thaumatin, glycyrrhizin, sucralose, dihydrochalcones, alitame, miraculin, monellin, stevioside (stevside) and neotame (neotame).

Suitable sweeteners may be selected from sugar alcohols, such as sorbitol, xylitol; monosaccharides, including sugar extracted from sugar cane and sugar beets (sucrose), dextrose (also known as glucose), fructose (also known as levulose), and lactose (also known as milk sugar); sorbitol, mannitol, glycerol, xylitol, erythritol, maltitol syrup (or hydrogenated starch hydrolysates), isomalt, lactitol; and mixtures of sugars, including glucose syrups (e.g., starch hydrolysates, mixtures containing dextrose, maltose, and a range of complex sugars); invert syrups (e.g., sucrose with a mixture of dextrose and fructose converted by an invertase (also known as sucrase or β -fructofuranosidase)), high sugar content syrups (e.g., molasses and honey with a particular mixture of levulose, dextrose, maltose, lactitol, sucrose, resin, dextrin and high sugars); and malt or malt extract.

The flavoring and aroma additives may comprise one or more synthetic or natural taste-masking flavors or aromatizing agents. The flavoring and perfuming agents may be selected from essential oils, including distillates, solvent extracts or cold pressed extracts of cut flowers, leaves, peels or whole fruits mashed into a paste, comprising a mixture of alcohols, esters, aldehydes and lactones; essences, including dilute solutions of essential oils or mixtures of synthetic chemical agents blended to match the natural aroma of fruits (e.g., strawberries, raspberries, and black currants); artificial and natural brew and wine flavors such as cognac brandy, whisky, rum, gin, sherry, boehringer's wine, and wine; tobacco, coffee, tea, cocoa and mint; fruit juices, including squeezed juices from washed, wiped fruits such as lemon, orange, and lime; spearmint, peppermint, wintergreen, cinnamon, cocoa, vanilla, licorice, menthol, eucalyptus, anise, nuts (e.g. peanut, coconut, hazelnut, chestnut, walnut, kola), almond, raisin; and powders, flours or plant material parts, including tobacco plant parts, such as nicotiana plant parts, and ginger in amounts that do not significantly affect nicotine levels.

The coloring additive may be selected from dyes approved for use in food additives.

The stabilizing additive may be selected from antioxidants including vitamin E (i.e. tocopherol), ascorbic acid, sodium metabisulphite, butylated hydroxytoluene, butylated hydroxyanisole, edetic acid and edetate; and preservatives, including citric, tartaric, lactic, malic, acetic, benzoic, and sorbic acids. Preferred embodiments comprise an antioxidant as a stabilizer, more preferably the antioxidant vitamin E and/or Butylated Hydroxytoluene (BHT).

Methods for delivering nicotine in any form to a subject

The present invention can be used to deliver nicotine to a subject (human) in a variety of ways. According to one embodiment of the invention, a method for delivering nicotine in any form to a subject comprises the steps of:

a) administering to a subject an oral formulation according to the invention containing nicotine in any form into the oral cavity of the subject, and

b) if desired, the nicotine in any form of the oral formulation is allowed to be released in the saliva of the mouth and absorbed into the plasma of the subject.

The method for delivering nicotine in any form may further comprise the steps of:

c) administering nicotine in any form to a subject in a continuous manner over a period of time. This period of time may be at least 5, 10, 20, 30 or 40 minutes.

Method for achieving a reduction in the urge to smoke or use tobacco

Another feature of the invention is the ability to use the invention to reduce the urge to smoke. The method according to the invention for achieving a reduction in the urge to smoke or use a nicotine-containing tobacco product and/or providing smoking satisfaction without smoking comprises the steps of:

a) at least partially replacing a nicotine-containing tobacco product with a tobacco-free nicotine-containing oral formulation,

b) administering to a subject an oral formulation comprising nicotine in any form into the oral cavity of the subject, and

c) if desired, the nicotine in any form of the oral formulation is allowed to be released in the saliva of the mouth and absorbed by the subject.

In another embodiment, the method according to the invention further comprises the step of administering nicotine in any form to the subject in a continuous manner over a period of time. This period of time may be at least 5, 10, 20, 30 or 40 minutes.

Other embodiments of methods for delivering nicotine to a subject may include the step of combining administration of an oral formulation with at least one other method for achieving a reduction in the urge to smoke or use tobacco.

The nicotine-containing material may be a material used, for example, for smoking, snuffing, or chewing, and may include cigarettes, cigars, pipe tobacco, snuff, smokeless tobacco (snus), and chewing tobacco.

Sustained reduction of desire to smoke or use tobacco

The invention may also be used to reduce the urge to smoke or use tobacco. It can also be used to provide a subject with sustained feeling or sensation of satisfaction and avoid restoring craving, which can be achieved after initial craving relief. Sustained craving relief can be achieved by using the oral formulation in a manner such as to allow for sustained nicotine absorption. As long as the subject's plasma nicotine level is maintained at a level sufficient to achieve such sensory perception, the subject's sustained craving relief and/or satisfied perception or sensation will continue.

The subject may achieve this by using an oral formulation over a period of time (e.g. 5, 10, 20, 30 or 40 minutes or more), for example by controlled release (e.g. by divided dose use) resulting in a slow release of nicotine.

Stopping the desire to smoke or use tobacco

For some users, the goal may be to stop nicotine use altogether for several reasons, such as health, economic, social, or behavioral reasons. Cessation of smoking or the desire to use tobacco can be achieved by gradually further reducing the amount of nicotine in any form over time. In an embodiment of the present invention, the method for achieving craving relief may further comprise the step of gradually decreasing the nicotine content of the oral formulation over time so as to achieve complete craving relief from tobacco.

Different types of smokers achieve a perception of decreased cravings at different plasma nicotine levels. This of course affects the respective type of administration regimen of the oral formulation according to the invention. Different types of smokers include, for example, peak purchasers or smokers who crave plasma nicotine levels steadily above withdrawal levels.

One strategy may be to reduce the frequency of administration of oral formulations. Other embodiments include varying the nicotine dosage in the oral formulation and combining the two means. Additionally, the strategy may include an oral formulation that is substantially free of any form of nicotine. Such oral formulations may be administered at the end of the treatment period when craving is low or substantially absent.

System for delivering nicotine and achieving craving relief

According to the present invention, there is a system for delivering nicotine in any form to a subject, in particular for achieving craving relief. Such a system comprises an oral formulation according to the invention and at least one other means for achieving a reduction in the urge to smoke.

Another system according to the invention may also be a system for achieving a reduction in the urge to smoke or use tobacco and/or providing smoking satisfaction without smoking. Such a system comprises an oral formulation according to the invention and at least one other method or means for achieving a reduction in the urge to smoke or use tobacco. Other methods and means may also be concomitant or simultaneous selected from: by oral spray, nasal spray, transdermal patch, inhalation device, lozenge, tablet and parenteral methods, subcutaneous methods and transmucosal methods; or tobacco may be used.

In particular embodiments, at least one other method comprises administering nicotine.

Use of oral formulations

As mentioned above, the use of the oral formulation according to the invention may comprise achieving a rapid and/or sustained reduction and/or a complete reduction in the urge to smoke and use tobacco, or to provide a sensation of smoking without smoking.

The dosage of nicotine is selected such that the effect of any form of nicotine gives the subject a unique perception and satisfaction. The use of oral formulations may also be in accordance with the present invention, alone or in combination with other means or methods known in the art of drug abuse. In particular, the present invention may be used in combination with other means described in the methods of the preceding paragraphs.

Such use can cause a rapid reduction in the urge to smoke or use tobacco. Other embodiments include a slow reduction in the urge to smoke or use tobacco.

Therapeutic and treatment uses

The oral formulations according to the invention are useful in therapy and treatment. The treatment may be treatment of a disease selected from: tobacco or nicotine dependence, Alzheimer's disease, Crohn's disease, Parkinson's disease, Tourette's syndrome, ulcerative colitis and weight control after cessation of smoking.

Nicotine may also be used in the oral formulations according to the invention to treat said diseases.

Furthermore, nicotine can be used for the preparation of an oral formulation comprising nicotine according to the invention for the treatment of said diseases.

Preparation of oral formulations

The oral formulations according to the invention are prepared essentially according to methods known in the art. Illustrative but non-limiting methods of preparation are set forth belowExamples of the inventionThe method of (1).

UnderExamples of the inventionDescribed in (1) is mixing, rolling and furrowing of chewing gum and compression of chewing gum. The followingExamples of the inventionInformation regarding the preparation of other embodiments of the present invention is also provided.

Conveniently, the additive composition (e.g. buffer system) according to the invention may be prepared simultaneously according to methods known in the art for formulating, for example, buffers. The buffer system may conveniently be added with the liquid portion of the composition or with the solid portion of the composition, depending on the physical characteristics of the buffer system incorporated. In the case of buffer systems obtained as fine powders, it is of course most convenient to add those powders together with the solid powder fraction of the other additives. The final product was then analyzed and packaged.

Analysis of nicotine

Analysis of the absorption and effect of nicotine according to the invention can be performed according to standard methods known in the art, e.g. using bioassays for determining nicotine or its metabolites in the plasma of a subject.

Examples of the invention

The following examples are illustrative and non-limiting with respect to embodiments of the present invention. Other embodiments of the invention are also envisaged by the skilled person, based on the following examples. The batches used to prepare the following formulations may vary according to actual needs and actual production equipment. If not otherwise stated, processes and equipment known in the art are used for the following preparations.

In the examples below, the amino acids used are L-arginine, glycine and N-glycylglycine. The skilled person may consider exchanging L-arginine, glycine and N-glycylglycine for one or more other amino acids, e.g. selected from table 1 above, thus changing the amount of amino acids according to existing methods. Furthermore, the skilled person can easily calculate whether a pH adjusting compound needs to be added. Thus, in some of the examples below, a pH adjusting compound is added in addition to the buffer.

EXAMPLE 1 tablet

275mg tablet with 2mg nicotine

Composition (I)	Amount in composition (mg)
		Nicotine bitartrate dihydrate	6.1

Composition (I)	Amount in composition (mg)
		L-arginine	17.9
Mannitol	210.9
		Xanthan gum	11.0
Crosslinked polyvinylpyrrolidone	11.0
		Flavoring agent	9.9
Aspartame	1.6
		Acesulfame potassium	1.1
Magnesium stearate	5.5

Preparation process：

Mixing the above components. The blend is then compressed into tablets by direct compression according to methods known in the art.

EXAMPLE 2 Orodispersion

This is a tablet intended to melt in the mouth when the melt material adheres to the oral mucosa where nicotine is deposited to enter the tissue.

400mg orally-meltable tablet with 2mg nicotine

Composition (I)	Relative amount in the composition (% w/w)
		Nicotine bitartrate dihydrate	1.5
Cocoa powder	35.0
		Vegetable oil	41.6
L-arginine	4.5
		Mannitol	10.4
Titanium dioxide	2.7
		Soybean lecithin	1.0
Aspartame	0.4

Composition (I)	Relative amount in the composition (% w/w)
		Acesulfame potassium	0.2
Flavoring agent	2.7

Preparation process：

The preparation of the formulation is carried out at room temperature. A portion of the fat component (i.e., vegetable oil) is melted. The solid components (i.e., nicotine salt, cocoa powder, buffering agents, mannitol, titanium dioxide, sweeteners, and flavoring agents) are added and mixed. The reduction of the particle size of the solid component is carried out by grinding the mixture in a roll refiner. If the solid component has reached the desired particle size, such as by grinding prior to mixing with the fat component, roll refining may be eliminated. After possible roll refiner treatment, the mixture is mixed with the rest of the melted vegetable oil or the mixture is re-melted (upon solidification) and mixed with the rest of the melted vegetable oil. The mixing of the melts is carried out in a suitable stirrer. The liquid component, i.e. soy lecithin, is added.

Tablets are then formed by suitable techniques such as moulding, extrusion or coagulation including pastillation after appropriate pre-treatment if desired. Other suitable methods of preparation known in the art may also be used.

Example 3A mouth spray

Nicotine mouth spray containing 14.3mg nicotine per ml and having pH of 9.0

Composition (I)	mg/ml
		Nicotine free base	14.3
Ethanol	100.0
		Propylene glycol	150.0
Glycerol	25.0
		L-arginine	58.3
Sodium bicarbonate	14.3
		Poloxamers	40.0
L-menthol	10.0
		Flavoring agent	4.0
Cooling agent	3.0
		Sweetening agent	3.0

Composition (I)	mg/ml
		Hydrochloric acid	Adding to pH 9.0
Purified water	Proper amount of

Example 3B mouth spray

Nicotine mouth spray containing 14.3mg nicotine per ml and having pH of 9

Batch production: 1000ml

Composition (I)	mg/ml
		Nicotine free base	14.3
Ethanol	100.0
		Propylene glycol	150.0
Glycerol	25.0
		Glycine or L-arginine	25.0 or 58.3
Sodium bicarbonate	14.3
		Poloxamers	40.0
L-menthol	10.0
		Flavoring agent	4.0
Cooling agent	3.0
		Sweetening agent	3.0
Hydrochloric acid	Adding to pH 9.0
		Purified water	Proper amount of

In examples 3A and 3B, and in some of the examples below, the pH-adjusting ability of the amino acid buffer was increased by adding a sufficient amount of a pH-adjusting compound.

Preparation process：

Mixture 1

1. Purified water was charged into the vessel.

2. Poloxamer is added, which should be dissolved during the mixing process before going to the next step.

3. Adding sweetener, glycine (or L-arginine) and sodium bicarbonate.

4. Agitation was continued until all components were dissolved.

Mixture II

5. The ethanol is filled into a container.

6. Levomenthol was added and agitation was continued until dissolved.

7. Propylene glycol, flavoring agent, glycerin and cooling agent are added. Stirring was continued until the solution was homogeneous.

Final mixing

8. Mixture 2 was poured into mixture 1 and stirred until a homogeneous solution was obtained.

9. Nicotine was added to the solution while gently stirring.

10. The pH of the solution was measured. The pH was adjusted to 9 by addition of hydrochloric acid.

11. Adding a proper amount of purified water to batch. The solution was stirred until a clear solution was obtained.

Example 4 capsules

Nicotine soft capsule 2mg

Composition (I)	％(w/w)
		The core component: nicotine free base medium chain triglyceride flavor and sweetener L-arginine colloidal silica inner shell component: sucrose fatty acid ester hydrogenated vegetable oil hull component: porcine gelatin sorbitol glycerol	2.2％86.6％7.8％2.9％0.5％60.0％40.0％80.0％18.0％2.0％
The weight ratio is as follows: core/inner shell/outer shell	64/30/6
		The total weight of the capsule is as follows:	142mg

use of：

The seamless soft capsule is a soft gelatin capsule characterized by a spherical, thin and seamless gelatin shell layer. The thin shell layer makes the capsule suitable for use in orally dissolving products, as compared to conventionally produced soft gelatin capsules intended for chewing or swallowing.

Preparation process：

Seamless soft capsules are prepared by forming droplets consisting of two or more concentric layers. The droplets are formed by feeding different liquids through concentric nozzles. The outermost nozzle provides a hydrophilic solution consisting of gelatin and additives such as plasticizers. The one or more internal nozzles provide a lipophilic liquid (e.g., fats, triglycerides) in which one or more active substances are dispersed. The lipophilic center and hydrophilic periphery of the formed droplets ensure good phase separation between the shell and core contents. The formed capsules are then subjected to subsequent processing steps, such as cooling, drying, washing and selection of size and shape.

Example 5A hard candy

Nicotine hard candy with 2mg nicotine

Composition (I)	％(w/w)
		Purified water	-
Isomalt	78.0
		75% solution of maltitol	19.5
Nicotine bitartrate dihydrate	0.2
		L-arginine	1.6
Flavoring agent	0.7
Total of	100.0

The block weight was 3.5g

Nicotine/block 2mg

Preparation process：

1. Purified water, isomalt and maltitol solutions were added to stainless steel beakers. Mixing and heating are carried out during continuous mixing.

2. The heating was stopped and cooled to 135-140 ℃. Nicotine bitartrate dihydrate was added and mixed until completely dispersed. L-arginine was added at 120 ℃ and mixed until dispersed.

3. Add flavor and mix until uniform.

4. Poured into a mold and allowed to cool.

Example 5B hard candy

Nicotine hard candy with 2mg nicotine

Composition (I)	％(w/w)
		Purified water
Isomalt	78.0
		75% solution of maltitol	15.2
Nicotine bitartrate dihydrate	0.6
		N-glycylglycine	3.2
Sodium carbonate	1.0
		Flavoring agent	2.0
Total of	100.0

The block weight was 1.0g

Nicotine/block 2mg

Preparation process：

1. Purified water, isomalt and maltitol solutions were added to stainless steel beakers. Mixing and heating are carried out during continuous mixing.

2. The heating was stopped and cooled to 135-140 ℃. Nicotine bitartrate dihydrate was added and mixed until completely dispersed. N-glycylglycine, sodium carbonate were added and mixed at 120 ℃ until dispersed.

3. Add flavor and mix until uniform.

4. Poured into a mold and allowed to cool.

EXAMPLE 6 oral films

Nicotine bilayer film with 2mg nicotine

Preparation Process (part 1)

1. Pullulan, xanthan gum, locust bean gum, carrageenan and pectin are mixed together.

2. Hot water was added to the mixture.

3. Sucralose and sorbitol were added and mixed until dissolved. And cooling to room temperature.

4. Polysorbate 80, Atmos 300, colorant, menthol and flavoring were premixed and added to the blend.

5. Tartaric acid and then nicotine free base were added and mixed.

6. The pullulan solution was cast on a substrate of the desired thickness and dried with hot air.

Preparation Process (part 2)：

1. Pullulan, xanthan gum, locust bean gum, carrageenan, pectin, L-arginine and sodium carbonate are mixed together.

2. Hot water was added to the mixture.

3. Sucralose and sorbitol were added and mixed until dissolved. And cooling to room temperature.

4. Polysorbate 80, Atmos 300, colorant, menthol and flavoring were premixed and added to the blend.

5. The pullulan solution was cast on a substrate of the desired thickness and dried with hot air.

Preparation (part 3)

1. The cast film (containing the active ingredient) and the cast film (containing the buffer) were laid on top of each other and pressed gently together.

2. And cutting into required size. Such as 24mm x 33mm, are suitable.

If necessary, a barrier layer may be placed between the injection-moulded film containing the active ingredient and the injection-moulded film containing the buffer agent in order to avoid chemical reactions between the two films.

Multiple layers of oral films are also contemplated.

Example 7 chewing Gum

Has the advantages ofNicotine chewing gum containing 1mg nicotine

Composition (I)	Grams per granule
		Isomalt	3.7
Sweetening agent	1.0
		Water (W)	0.1
Pectin	0.1
		L-arginine	0.036
Flavoring agent	0.1
		Nicotine bitartrate dihydrate	0.0032
Total of	5g

Preparation process：

1. Isomalt is heated to the melting point and sweetener is added and the mixture is allowed to cool.

2. Adding pectin solution, L-arginine and flavoring agent to the cooled mixture.

3. Adding nicotine bitartrate dihydrate, and mixing.

4. Injection molding with starch of the desired shape and size using methods known in the art.

Example 8 chewy sweets

Nicotine chewy candy with 1mg nicotine

Composition (I)	Grams per granule
		Isomalt	3.4
Sweetening agent	1.0
		Water (W)	0.1

Composition (I)	Grams per granule
		Vegetable oil	0.3
Glyceryl monostearate	0.1
		L-arginine	0.036
Flavoring agent	0.1
		Nicotine bitartrate dihydrate	0.0032
Total of	5g

Preparation process

1. Isomalt is heated to the melting point and sweetener is added and the mixture is allowed to cool.

2. Adding vegetable oil, L-arginine and flavoring agent to the cooled mixture. And (4) fully mixing.

3. Nicotine bitartrate dihydrate was added. And (4) fully mixing. Injection molded or extruded in a mold and cut to the desired dimensions using methods known in the art.

Example 9A compressed chewing gum

Example 9A

Compressed chewing gum containing nicotine with 2mg nicotine

Composition (I)	Amount in composition (mg)
		Nicotine Resin Complex (NRC) 20%	10
Chewing gum base	556
		L-arginine	36
Sodium carbonate	Proper amount of
		Castor oil	60
Sorbitol	140
		Flavoring agent	118
Sweetening agent	5
		Colloidal silica	22.5

Magnesium stearate	20
		Talc	22.5
Sodium bicarbonate	Proper amount of

Preparation process：

1) The nicotine resin complex is blended with a hydrophilic water soluble ingredient, i.e., sorbitol.

2) The hydrophobic component, i.e. castor oil, which is practically insoluble in water, is heated to a suitable temperature until a solution is obtained.

3) The blend obtained in 1) is added to solution 2) with vigorous stirring.

4) Cooling the blend of 3) above below room temperature and blending with a chewing gum base and other additives.

5) If necessary, the blend of 4) above is sieved to remove agglomerates and pressed into chewing gum by direct compression.

Example 9B

Nicotine compressed chewing gum with 2mg nicotine

Composition (I)	Amount in composition (mg)
		Nicotine resin composition 20%	10
Chewing gum base	300
		L-arginine	36
Sodium carbonate	Proper amount of
		Isomalt	95
Sorbitol	491
		SeasoningAgent for treating cancer	30
Sweetening agent	3
		Colloidal silica	5
Magnesium stearate	20
		Sodium bicarbonate	Proper amount of

Description of the preparation：

1) Mixing: a chewing gum base powder mixture comprising a chewing gum base, a sweetener, and a glidant is blended with an active, a flavoring agent, a glidant, an artificial sweetener, a buffering agent, and a lubricant.

2) Tabletting: if necessary, the above blend is sieved to remove agglomerates and compressed into chewing gum by direct compression.

EXAMPLE 10 chewing gum preparation by mixing, Rolling and furrowing

Preparation process：

Mixing, rolling and grooving are accomplished by conventional methods. A double sigma blade mixer was used to mix the gum base with the other components of the formulation. The gum base was softened in a mixer. The gum base becomes plastic by heating (with a heating mantle) and mixing. Thus, the softened matrix can be mixed with the liquid component and the solid material as a powder mixture. The warm slugs are removed as slugs stacked on pallets on a cart and stored in the conditioned area until the next step is initiated. This is used to cool the chewing gum.

Thereafter, rolling and grooving are performed. Chewing gum is extruded into thick candy pieces which are rolled to the appropriate thickness by sets of calender rolls. Grooved rollers (usually two sets) cut the sugar sheet into appropriately sized pieces.

The sugar tablets are then transferred to a tray in an air-conditioned area where the sugar tablets are cooled so that they are brittle enough to break. The gum slabs from the air conditioning area are then passed through a breaker, which is a rotating drum, which separates the slabs into individual gum pieces along the flutes.

The deformed chewing gum is sorted out in a sorting step. Acceptable chewing gum was further inspected by passing it through a metal detector.

Claims (40)

1. A buffered nicotine-containing oral pharmaceutical formulation, characterized in that it is buffered with at least one amino acid and/or a salt thereof, and in that it comprises a pH-adjusting compound when the pH-adjusting ability of the at least one amino acid and/or salt thereof is insufficient.

2. The oral formulation according to claim 1, characterized in that among the at least one amino acid, at least one endogenous amino acid is present.

3. The oral formulation according to claim 2, characterized in that said at least one endogenous amino acid is selected from arginine, asparagine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, serine, threonine and valine.

4. The oral formulation according to claim 3, characterized in that said at least one endogenous amino acid is selected from the group consisting of asparagine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, methionine, phenylalanine, serine, threonine and valine.

5. The oral formulation according to claim 1, characterized in that said at least one amino acid is selected from the group consisting of cysteic acid, glycylglycine and ornithine.

6. The oral formulation of any one of the preceding claims, buffered in such a way that upon oral administration of the oral formulation to a subject the pH of the saliva of the subject will increase by 0.2-4 pH units.

7. The oral formulation of claim 6, buffered in such a way that upon administration of the oral formulation to a subject the pH of the saliva of the subject will increase by 0.5-2 pH units.

8. The oral formulation according to any one of the preceding claims, which is buffered with an amino acid together with one or more buffers and/or one or more pH adjusting compounds selected from the group consisting of: alkali metal or ammonium carbonates such as potassium or sodium, including bicarbonates or sesquicarbonates, glycinates, phosphates, glycerophosphates or citrates, including trisodium phosphate, disodium hydrogen phosphate; tripotassium phosphate, dipotassium phosphate, calcium hydroxide, sodium glycinate and tromethamine; and mixtures thereof.

9. The oral formulation of any one of claims 1-8, wherein the nicotine in any form is selected from the group consisting of: nicotine salt, nicotine in free base form, nicotine derivatives such as nicotine cation exchangers, nicotine inclusion complexes or any non-covalently bound nicotine; nicotine bound to zeolite; nicotine bound to cellulose or starch microspheres; and mixtures thereof.

10. An oral formulation according to claim 9, wherein the nicotine inclusion complex is a cyclodextrin complex, such as b-cyclodextrin.

11. The oral formulation of claim 9, wherein the nicotine cation exchanger is a polyacrylate cation exchanger.

12. The oral formulation of claim 9, wherein the nicotine salt is a mono-tartrate, hydrogen tartrate, citrate, malate, and/or hydrochloride salt.

13. The oral formulation of any one of claims 1-10, wherein the nicotine in any form is present in an amount of 0.05-8mg calculated as nicotine in free base form per unit dose.

14. The oral formulation of claim 13, wherein the nicotine in any form is present in an amount of 0.1-6mg calculated as nicotine in free base form per unit dose.

15. The oral formulation of claim 14, wherein the nicotine in any form is present in an amount of 2-5mg calculated as nicotine in free base form per unit dose.

16. The oral formulation of any one of claims 1-15, wherein optionally at least one or more additives are selected from: solvents, co-solvents, stabilizers, preservatives, antioxidants, emollients, thickeners, binders, fillers, solubilizers, gums, lipid barriers, film formers, emulsifiers, glidants, lubricants, coating agents, melting media, sweeteners, flavoring agents, fragrances, cooling agents, enhancers, colorants, vitamins, minerals, fluorine, breath fresheners, tooth whiteners, and mixtures thereof.

17. The oral formulation of any one of claims 1-16, in the form of: a mouth spray, a capsule, a chewing gum, a chewable tablet, a tablet, an orally disintegrating tablet, a lozenge, a hard candy, a chewy candy, a gummy candy, or a buccal film.

18. The oral formulation of any one of claims 1-17, which is uncoated.

19. A method for delivering nicotine in any form to a subject, the method comprising the steps of:

a) administering to a subject the oral formulation of any one of claims 1-18 into the oral cavity of the subject, an

b) If desired, allowing said nicotine in any form of said oral formulation to be released in saliva of said oral cavity and absorbed into the systemic circulation of said subject.

20. A system for delivering nicotine in any form to a subject, the system comprising an oral formulation of any one of claims 1-18 and at least one other means or method for achieving a reduction in the urge to smoke or use tobacco.

21. A system for achieving a reduction in the urge to smoke or use tobacco and/or providing smoking satisfaction without smoking, the system comprising an oral formulation of any one of claims 1-18 and at least one other means or method for achieving a reduction in the urge to smoke or use tobacco.

22. The system of claim 20 or 21, wherein the at least one other means or method is concomitant or concurrent with a means or method selected from: by oral spray, nasal spray, transdermal patch, inhalation device, lozenge, tablet and parenteral methods, subcutaneous methods and transmucosal methods; or tobacco may be used.

23. The system of claim 22, wherein the at least one other means or method comprises administering nicotine.

24. Use of an oral formulation according to claims 1-18 for achieving a rapid reduction and/or a sustained reduction and/or a complete reduction in the urge to smoke or use tobacco and/or for providing smoking satisfaction without smoking.

25. Use of an oral formulation of any one of claims 1-18 for delivering nicotine in any form to a subject.

26. A nicotine-containing tablet comprising nicotine bitartrate dihydrate, an amino acid, mannitol or a filler, xanthan gum or another binder, cross-linked polyvinylpyrrolidone or another disintegrant, one or more flavoring agents, and one or more artificial sweeteners.

27. A nicotine-containing oral melt tablet comprising nicotine bitartrate dihydrate, cocoa powder or another filler/texturizer/taste-masking agent, vegetable oil or another melting medium, amino acids, mannitol or another diluent, soy lecithin or another emulsifier, a coloring agent, an artificial sweetener and a flavoring agent.

28. A nicotine-containing oral spray comprising nicotine free base, ethanol or another solvent, an amino acid, a poloxamer or another solubilizer, edetate disodium or another stabilizer, and an artificial sweetener.

29. A nicotine-containing soft capsule comprising a nicotine free base, a medium chain triglyceride or another lipophilic carrier, a flavoring agent, an amino acid and a thickening agent in the core, a hydrophilic shell-forming material in the inner shell and a shell-forming material and a softening agent in the outer shell.

30. A nicotine-containing hard candy comprising nicotine bitartrate dihydrate, isomalt, maltitol, an amino acid and a flavoring agent.

31. An oral film comprising nicotine, said oral film comprising nicotine bitartrate dihydrate, xanthan gum, locust bean gum, carrageenan, pectin, pullulan, an amino acid, polysorbate, an artificial sweetener, and a flavoring agent.

32. A nicotine-containing chewing gum comprising nicotine bitartrate dihydrate, isomalt, pectin, an amino acid, an artificial sweetener and a flavoring agent.

33. A nicotine-containing chewy sweet comprising nicotine bitartrate dihydrate, isomalt, vegetable oil, amino acids, sweeteners and flavourings.

34. A nicotine-containing chewing gum, the chewing gum being prepared by direct compression, the chewing gum comprising: nicotine resin complex, chewing gum base, amino acids, one or more sweeteners, artificial sweeteners, glidants, flavors and lubricants, and optionally a hydrophobic agent.

35. A nicotine-containing chewing gum prepared by mixing, rolling and furrowing, the chewing gum comprising: nicotine resin complex, gum base, sweetener, flavoring agent, and amino acid.

36. The formulation of any one of claims 26-35, wherein the amino acid is exchanged for an amino acid in combination with a buffer selected from the group consisting of: alkali metal or ammonium carbonates such as potassium or sodium, including bicarbonates or sesquicarbonates, glycinates, phosphates, glycerophosphates or citrates, including trisodium phosphate, disodium hydrogen phosphate; tripotassium phosphate, dipotassium phosphate, calcium hydroxide, sodium glycinate and tromethamine; and mixtures thereof.

37. A formulation according to any one of claims 1 to 18 or a formulation according to any one of claims 25 to 36 for use in therapy.

38. The formulation of claim 37, wherein the treatment is the management of a disease selected from the group consisting of: tobacco or nicotine dependence, Alzheimer's disease, Crohn's disease, Parkinson's disease, Tourette's syndrome, ulcerative colitis and weight control after cessation of smoking.

39. Use of nicotine for the preparation of a product according to any of claims 1-18 or a product according to any of claims 26-36 for the treatment of a disease selected from the group consisting of: tobacco or nicotine dependence, Alzheimer's disease, Crohn's disease, Parkinson's disease, Tourette's syndrome, ulcerative colitis and weight control after cessation of smoking.

40. Use of nicotine for the preparation of an oral formulation according to any one of claims 1-18 or an oral formulation according to any one of claims 26-36 for the treatment of a disease selected from: tobacco or nicotine dependence, Alzheimer's disease, Crohn's disease, Parkinson's disease, Tourette's syndrome, ulcerative colitis and weight control after cessation of smoking.